Years later, Frankenstein, now going by the alias of Dr. Stein, has become a successful physician in Carlsbruck, catering to the wealthy while also attending to the poor in a paupers' hospital. Dr. Hans Kleve, a junior member of the medical council, recognises him and blackmails him into allowing him to become his apprentice.

Together with Karl, the hunchback who facilitated Frankenstein's escape, Frankenstein and Kleve continue with the Baron's experiment: transplanting a living brain into a new body—one that isn't a crude, cobbled-together monster. The deformed Karl is more than willing to volunteer his brain, thereby gaining a new, healthy body—particularly after meeting the new assistant at the hospital, the lovely Margaret.

The transplant succeeds, but when the excited Dr. Kleve tells Karl that he will be a medical sensation, Karl panics and convinces Margaret to free him. Kleve notes that the chimpanzee that Frankenstein transplanted with the brain of an orangutan ate its mate and worries about Karl, but his concerns are brushed off by Frankenstein.

Karl flees from the hospital and hides in Dr. Stein's laboratory, where he burns his preserved hunchback body. He is attacked by the drunken janitor, who takes him for a burglar, but manages to strangle the man. Frankenstein and Kleve discover Karl is missing and begin searching for him.

The next morning, Margaret finds Karl in her aunt's stable. While she goes to fetch Dr. Kleve, Karl experiences difficulties with his arm and leg. When Kleve and Margaret arrive, he is gone. At night, he ambushes and strangles a local girl. The next night, he rushes into an evening reception. Having redeveloped his deformities, he pleads Frankenstein for help, using his real name, before collapsing.

Frankenstein, disregarding Kleve's pleas that he should leave, appears before the medical council, where he denies being the infamous Baron Frankenstein. The unsatisfied councillors exhume Frankenstein's grave only to discover the priest's body, concluding that the real Frankenstein is still alive.

At the same time, frightened and angry patients at the hospital brutally attack Frankenstein and leave him for dead. Kleve rescues his dying mentor and rushes him to the laboratory, where he extracts Frankenstein's brain from his body just before the police arrive. Kleve shows them Frankenstein's dead body, claiming that he tried in vain to save his life. Alone again and uneasy about his skills, Kleve begins transplanting the brain into another body—one that Frankenstein had been preparing earlier and which was made to resemble him...

The film was shot at Bray Studios, back-to-back with Dracula (1958), which likewise starred Cushing and was directed by Fisher. Both films used many of the same sets. Thus, for example, Dracula's crypt became Frankenstein's surgery, and the castle exterior became the outside of the Baron's laboratory.

Two novelisations of the film were published. The first one by Jimmy Sangster (using the penname Hurford Janes) was published by Panther Books in 1958; the second was by John Burke as part of his 1966 Pan book The Hammer Horror Film Omnibus. A third novelisation, by Shaun Hutson is scheduled for publication by Hammer Books in March 2013 (ISBN 9780099556237).

Like its predecessor, The Revenge of Frankenstein has been well received by critics, and currently holds a 92% approval rating on movie review aggregator website Rotten Tomatoes based on eight reviews.[2]

Motion Picture Daily noted, "a horror picture turned out with creative skill and imagination. The most notable contribution the Hammers have made to the genre is their stunning use of color for frightening effects. . . (Hammer) have demolished once and for all the theory that horror films should always be in black-and-white."[3]